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NASA NTRS1999

Exercise Countermeasures for Bone Loss During Space Flight: A Method for the Study of Ground Reaction Forces and their Implications for Bone Strain

Effective countermeasures to prevent loss of bone mineral during long duration space flight remain elusive. Despite an exercise program on MIR flights, the data from LeBlanc et al. (1996) indicated that there was still a mean rate of loss of bone mineral density in the proximal femur of 1.58% per month (n=18, flight duration 4 - 14.4 months). The specific mechanisms regulating bone mass are not known, but most investigators agree that bone maintenance is largely dependent upon mechanical demand and the resultant local bone strains. A plausible hypothesis is that bone loss during space flight, such as that reported by LeBlanc et al. (1996), may result from failure to effectively load the skeleton in order to generate localized bone strains of sufficient magnitude to prevent disuse osteoporosis. A variety of methods have been proposed to simulate locomotor exercise in reduced gravity. In such simulations, and in an actual microgravity environment, a gravity replacement load (GRL) must always be added to return the exercising subject to the support surface and the resulting skeletal load is critically dependent upon the magnitude of the GRL. To our knowledge, GRLs during orbital flight have only been measured once (on STS 81) and it is likely that most or all prior treadmill exercise in space has used GRLs that were less than one body weight. McCrory (1997) has shown that subjects walking and running in simulated zero-G can tolerate GRLs of 1 if an appropriate harness is used. Several investigators have attempted to measure in vivo strains and forces in the bones of humans, but have faced ethical and technical limitations. The anteromedial aspect of the tibial midshaft has been a common site for the placement of strain gauges; one reason to measure strains in the anterior tibia is that this region is surgically accessible. Aamodt et al. (1997) were able to measure strains on the lateral surface of the proximal femur only because their experimental subjects were already scheduled for hip surgery. Lu et al. (1997) used an instrumented massive proximal femoral prosthesis along with electromyographic measurements to demonstrate that femoral forces depend on muscular activity. These analyses of in vivo bone mechanics are valuable. The invasive nature of the procedures involved, however, limits both the number of subjects and the number of strain gauge locations. Further, the results of these studies may be confounded by the inclusion of subjects with pathological conditions. Gross et al. (1992) measured strain at three locations on the equine third metacarpal and used those data to construct a computer model of the internal strain environment of the bone. An analogous placement of multiple gauges in living humans would be difficult and potentially hazardous because of the depth of soft tissue overlying the tibia and femur.

Peterman, M.↗

NASA NTRSDate not supplied

The Effects of Spaceflight and Microgravity Exposure on Female Astronaut Health and Performance

Over the past half century, our understanding of the physiological effects of space exploration and microgravity exposure have improved immensely. Microgravity causes incredible changes to the human body that increase risk of injury upon return to Earth and lunar/planetary egress scenarios. This is due to deconditioning of the cardiovascular and skeletal muscle systems that reduce aerobic capacity and muscular strength. With upcoming exploration class missions, such as NASA’s Artemis lunar exploration program which aims to send the first female astronaut to the lunar surface by 2030, as well as a long-term goal of Martian exploration, maintaining astronaut health during extended-duration space flight is critical for achieving mission objectives. However, our understanding of these physiological implications due to microgravity are based primarily on flight studies of male astronauts and 1g bedrest analog study participants, with few investigations focusing specifically on females. Innate physiologic differences in endocrine signaling and reproductive function impact sex-dependent responses to various health conditions, treatments, and environmental factors in nearly every system in the body. Therefore, to assume comparable alterations in females in response to microgravity exposure may be inappropriate and consequentially, could lead to lasting impacts on female astronaut health and impact mission success. Moreover, differences in sex hormones may also influence the regulation of cardiovascular control during egress activity after space flight-induced deconditioning and blood volume loss (i.e., risk for orthostatic intolerance). Other potential physiological systems and factors related to musculoskeletal health and aerobic capacity that warrant investigation with respect to microgravity include endocrine/reproductive function, vascular control, bone mineral density/microarchitecture, and soft-tissue health. The purpose of this investigation is two-fold: 1) to summarize the data available from space flight and simulated bedrest analog exposures to begin addressing these gaps in knowledge regarding impacts to female astronaut health, and 2) to describe differences in demographic health characteristics, injury prevalence, and aerobic capacity and muscular strength in NASA female and male astronauts. Female astronauts make up 50% of Artemis-specific astronaut corps and the extent to which microgravity exposure impacts female cardiovascular and musculoskeletal health, and whether these alterations are consistent with their male counterparts, is inconclusive. With the growing inclusion of female astronauts in the NASA space program and the increased duration of missions beyond low Earth orbit, a greater understanding of the sex-specific adaptation to space travel will help determine the development of appropriate countermeasures for minimizing risk and maintaining health of all astronauts.

Nicole Christine Strock↗

NASA NTRS2023

The Effects of Space Flight and Microgravity Exposure on Female Astronaut Health and Performance

Over the past half century, our understanding of the physiological effects of space exploration and microgravity exposure have improved immensely. Microgravity causes incredible changes to the human body that increase risk of injury upon return to Earth and lunar/planetary egress scenarios. This is due to deconditioning of the cardiovascular and skeletal muscle systems that reduce aerobic capacity and muscular strength. With upcoming exploration class missions, such as NASA’s Artemis lunar exploration program which aims to send the first female astronaut to the lunar surface by 2030, as well as a long-term goal of Martian exploration, maintaining astronaut health during extended-duration space flight is critical for achieving mission objectives. However, our understanding of these physiological implications due to microgravity are based primarily on flight studies of male astronauts and 1g bed rest analog study participants, with few investigations focusing specifically on females. Innate physiologic differences in endocrine signaling and reproductive function impact sex-dependent responses to various health conditions, treatments, and environmental factors in nearly every system in the body. Therefore, to assume comparable alterations in females in response to microgravity exposure may be inappropriate and consequentially, could lead to lasting impacts on female astronaut health and impact mission success. Moreover, differences in sex hormones may also influence the regulation of cardiovascular control during egress activity after space flight-induced deconditioning and blood volume loss (i.e., risk for orthostatic intolerance). Other potential physiological systems and factors related to musculoskeletal health and aerobic capacity that warrant investigation with respect to microgravity include endocrine/reproductive function, vascular control, bone mineral density/microarchitecture, and soft-tissue health. The purpose of this investigation is two-fold: 1) to summarize the data available from space flight and simulated bed rest analog exposures to begin addressing these gaps in knowledge regarding impacts to female astronaut health, and 2) to describe differences in demographic health characteristics, injury prevalence, and aerobic capacity and muscular strength in NASA female and male astronauts. Female astronauts make up 50% of Artemis-specific astronaut corps and the extent to which microgravity exposure impacts female cardiovascular and musculoskeletal health, and whether these alterations are consistent with their male counterparts, is inconclusive. With the growing inclusion of female astronauts in the NASA space program and the increased duration of missions beyond low Earth orbit, a greater understanding of the sex-specific adaptation to space travel will help determine the development of appropriate countermeasures for minimizing risk and maintaining health of all astronauts.

Female Astronaut↗

NASA NTRSDate not supplied

The Effects of Space Flight and Microgravity Exposure on Female Astronaut Health and Performance

Over the past half century, our understanding of the physiological effects of space exploration and microgravity exposure have improved immensely. Microgravity causes incredible changes to the human body that increase risk of injury upon return to Earth and lunar/planetary egress scenarios. This is due to deconditioning of the cardiovascular and skeletal muscle systems that reduce aerobic capacity and muscular strength. With upcoming exploration class missions, such as NASA’s Artemis lunar exploration program which aims to send the first female astronaut to the lunar surface by 2030, as well as a long-term goal of Martian exploration, maintaining astronaut health during extended-duration space flight is critical for achieving mission objectives. However, our understanding of these physiological implications due to microgravity are based primarily on flight studies of male astronauts and 1g bed rest analog study participants, with few investigations focusing specifically on females. Innate physiologic differences in endocrine signaling and reproductive function impact sex-dependent responses to various health conditions, treatments, and environmental factors in nearly every system in the body. Therefore, to assume comparable alterations in females in response to microgravity exposure may be inappropriate and consequentially, could lead to lasting impacts on female astronaut health and impact mission success. Moreover, differences in sex hormones may also influence the regulation of cardiovascular control during egress activity after space flight-induced deconditioning and blood volume loss (i.e., risk for orthostatic intolerance). Other potential physiological systems and factors related to musculoskeletal health and aerobic capacity that warrant investigation with respect to microgravity include endocrine/reproductive function, vascular control, bone mineral density/microarchitecture, and soft-tissue health. The purpose of this investigation is two-fold: 1) to summarize the data available from space flight and simulated bed rest analog exposures to begin addressing these gaps in knowledge regarding impacts to female astronaut health, and 2) to describe differences in demographic health characteristics, injury prevalence, and aerobic capacity and muscular strength in NASA female and male astronauts. Female astronauts make up 50% of Artemis-specific astronaut corps and the extent to which microgravity exposure impacts female cardiovascular and musculoskeletal health, and whether these alterations are consistent with their male counterparts, is inconclusive. With the growing inclusion of female astronauts in the NASA space program and the increased duration of missions beyond low Earth orbit, a greater understanding of the sex-specific adaptation to space travel will help determine the development of appropriate countermeasures for minimizing risk and maintaining health of all astronauts.

Female Astronaut↗

NASA NTRSDate not supplied

A Multi Targeted Dietary Supplement as a Potential Countermeasure for Prolonged, Deep Space Exploration

Deep space exploration, particularly to the Moon and Mars, are currently major goals of NASA and other international space agencies. Long-term space flight presents unique challenges to the human physiology from microgravity, social isolation, altered circadian rhythm and radiation. Oxidative stress has been implicated as a crucial factor in space environment induced injury. Elucidating these detrimental effects on the central nervous system and brain is a primary objective, as they may result in adverse changes in astronaut behavior, mood and performance of critical tasks. We were recently funded by HRP Human Factors Behavioral Performance (HFBP) Element to test the hypothesis that Galactic Cosmic Ray Simulation (GCRsim) Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure and function, and neurobehavioral and cognitive performance. This project will identify potential biomarkers for, and mechanisms underlying, structural and functional changes in the immune and nervous systems leading to behavioral/cognitive performance deficits, and its potential application to develop effective countermeasures to mitigate negative health effects of long duration space habitation. Countermeasures to offset neurological damaged and cognitive deficits are paramount for protecting astronauts during deep space transits, but many countermeasures have been found to be unsuitable in ground-based model studies. We have developed a multi targeted dietary supplement (MTDS) designed to simultaneously ameliorate oxidative stress, inflammatory processes, energetic shortfalls, and membrane and mitochondrial deterioration. Administration of this MTDS has improved cognition and longevity in age accelerated and normal aging mice. Specifically, the MTDS was found to prevent a decline in mitochondrial complex III activity and cell loss, as well as prevent an increase in protein carbonyls and mitochondrial 3-nitrotyrosine in the brain of these mice. Further, administration of the MTDS was also found to reduce bone marrow chromosomal aberrations, DNA damage, lymphocyte apoptosis after whole body exposure of 2 Gy γ radiation. Mice exposed to a high dose cranially (10 Gy) had decreased cognitive responses (seen as increased latency time to uncover buried food and decreased novel object recognition), increased plasma 8-OHdG levels, increased markers of cell stress in the brain, decreased hippocampal brain-derived neurotrophic factor (BDNF) protein and decreased plasma levels of cytokines, all of which were ameliorated with treatment of the MTDS. As we have shown the supplement is protective in models of cognitive damage similar space environment stressors, particularly increased oxidative stress, we propose it may be a suitable countermeasure for upcoming deep space exploration.

radiation↗

NASA NTRSDate not supplied

A MULTI TARGETED DIETARY SUPPLEMENT AS A POTENTIAL COUNTERMEASURE FOR DEEP SPACE EXPLORATION

Future deep space exploration to the Moon and Mars and beyond are currently major goals of NASA. Space flight presents unique challenges to the human physiology from the combined effects of microgravity, social isolation, altered circadian rhythm and radiation. Oxidative stress has been implicated as a crucial factor in space environment induced injury. Elucidating these detrimental effects on the central nervous system and brain is a primary objective, as they may result in adverse changes in astronaut behavior, mood and performance of critical tasks. We were recently funded by HRP Human Factors Behavioral Performance (HFBP) Element to test the hypothesis that Galactic Cosmic Ray Simulation (GCRsim) Ionizing Radiation (IR), microgravity and social isolation combine synergistically to trigger an oxidative stress response that alters immune homeostasis, brain structure and function, and neurobehavioral and cognitive performance. This project will identify potential biomarkers for, and mechanisms underlying, structural and functional changes in the immune and nervous systems leading to behavioral/cognitive performance deficits, and its potential application to develop effective countermeasures to mitigate negative health effects of long duration space habitation. Countermeasures to offset neurological damaged and cognitive deficits are paramount for protecting astronauts during deep space transits, but many countermeasures have been found to be unsuitable in ground-based model studies. We have developed a multi targeted dietary supplement (MTDS) designed to simultaneously ameliorate oxidative stress, inflammatory processes, energetic shortfalls, and membrane and mitochondrial deterioration. Administration of this MTDS has improved cognition and longevity in age accelerated and normal aging mice. Specifically, the MTDS was found to prevent a decline in mitochondrial complex III activity and cell loss, as well as prevent an increase in protein carbonyls and mitochondrial 3-nitrotyrosine in the brain of these mice. Further, administration of the MTDS was also found to reduce bone marrow chromosomal aberrations, DNA damage, lymphocyte apoptosis after whole body exposure of 2 Gy γ radiation. Mice exposed to a high dose cranially (10 Gy) had decreased cognitive responses (seen as increased latency time to uncover buried food and decreased novel object recognition), increased plasma 8-OHdG levels, increased markers of cell stress in the brain, decreased hippocampal brain-derived neurotrophic factor (BDNF) protein and decreased plasma levels of cytokines, all of which were ameliorated with treatment of the MTDS. As we have shown the supplement is protective in models of cognitive damage similar space environment stressors, particularly increased oxidative stress, we propose it may be a suitable countermeasure for upcoming deep space exploration.

Stephanie Puukila↗

NASA NTRS2020

Development and Comparison of an Artificial Gravity Concept for Human Spaceflight

This Internship served as a resource to find specific research about the many facets of artificial gravity. With three main areas to be addressed in detail: the negative health effects of microgravity and how current mitigation methods fall short, the knowns and unknowns of artificial gravity as a countermeasure, and past artificial gravity habitat concepts. This report primarily focuses on the negative health effects of microgravity and how current mitigation methods fall short. Through NASA resources such as the NTRS, and external sources such as the AIAA, research papers were gathered that were pertinent to the topic. Each paper was uploaded to a NASA SharePoint and abstracts were drafted to highlight the important information. The expected results were to build a library of easily accessible information that would allow for Ryan Joyce and Gabe Merrill to easily get up to speed on relevant information. This process should allow for a faster period of understanding with high relevancy material. The ability to quickly reference data will help to build an informed and detailed case for any future proposals on artificial gravity. This also prevents the need to spend many hours searching for relevant documentation, allowing for more time to be dedicated to the creation process. The project has successfully met expectations and is continuing to add pertinent documentation. Current research shows great potential for artificial gravity as a countermeasure on long duration missions. The gravity like forces created in an artificial gravity ship could help to prevent serious problems such as muscle loss, bone fractures, vision loss due to increased intracranial pressure, and would allow for transition to other gravity environments with little to no recovery period. These conditions are highly favorable for long duration missions as current mitigation methods have yet to be proven beyond one year in space and often only slow symptoms instead of preventing them.

Alice Elberfeld↗

NASA NTRS1996

Ground Reaction Forces During Locomotion in Simulated Microgravity

Significant losses in bone density and mineral, primarily in the lower extremities have been reported following exposure to weightlessness. Recent investigations suggest that mechanical influences such as bone deformation and strain rate may be critically important in stimulating new bone formation. It was hypothesized that velocity, cadence and harness design would significantly affect lower limb impact forces during treadmill exercise in simulated zero gravity (0G). A ground-based hypogravity simulator was used to investigate which factors affect limb loading during tethered treadmill exercise. A fractional factorial design was used and 12 subjects were studied. The results showed that running on active and passive treadmills in the simulator with a tethering force close to the maximum comfortable level produced similar magnitudes for the peak ground reaction force. It was also found that these maximum forces were significantly lower than those obtained during overground trials, even when the speeds of locomotion in the simulator were 66 % greater than those in 1 G. Cadence had no effect on any of the response variables. The maximum rate of force application (DFDT-Max) was similar for overground running and exercise in simulated 0G, provided that the "weightless subjects ran on a motorized treadmill. These findings have implications for the use of treadmill exercise as a countermeasure for hypokinetic osteoporosis. As the relationship between mechanical factors and osteogenesis becomes better understood, results from human experiments in 0G simulators will help to design in-flight exercise programs that are more closely targeted to generate appropriate mechanical stimuli.

Davis, B. L.↗

NASA NTRSDate not supplied

Temporal Changes in Astronauts’ Muscle and Cardiorespiratory Physiology Before, During, and After Spaceflight

Background: NASA’s planned space exploration missions will require astronauts to safely perform extravehicular activity (EVA) and to safely egress vehicles in a variety of landing scenarios. Prolonged exposure to spaceflight can diminish tolerance for physical activity, decrease cardiovascular and sensorimotor function, cause loss of bone mineral density, as well as reduced muscle mass and strength. Although exercise can mitigate these spaceflight-induced physiological decrements, little is known regarding the time-course of changes in muscle and aerobic performance during spaceflight. Furthermore, these exercise countermeasures are not fully protective. For example, maximal aerobic capacity (VO2pk), lower body muscle cross-sectional area, and strength decrease by about 10% to 15% after short- (≈14 days) and long-duration (≈6 months) missions on the International Space Station (ISS). Future space missions longer in duration and further from Earth will employ exploration vehicles that will have exercise hardware with less robust and more constrained exercise capabilities than of those available on the ISS. Thus, countermeasures will need to be optimized to protect crew health and performance on exploration-class missions lasting up to 3 years. This requires a more detailed understanding of the dynamic effects of spaceflight on human health and performance, the ability of exercise to protect against this deconditioning, and the interaction of exercise with interrelated factors like nutrition, sleep, and environmental conditions. Methods: We will use standardized research and medical testing protocols previously validated in 1g and microgravity to quantify the time course and the inter-individual variability of changes in physical performance, including cardiorespiratory fitness and muscle strength and endurance, before, during, and after spaceflight missions lasting 2 months, 6 months, and 1 year. Additionally, we will use an extrapolation model to predict changes associated with multi-year exploration missions. Additionally, we will monitor in-flight exercise, nutrition, and sleep using in-flight assessment tools. Significance: Our testing protocols will provide valuable information for determining time course of change and the interindividual variability of spaceflight-induced deconditioning of aerobic capacity and muscle strength and endurance over the course of spaceflight missions up to and beyond 1 year. This information will be vital to assess whether humans can be physically ready for deep space exploration, such as on a mission to Mars, using current technology, or if additional mitigation strategies are necessary.

N Strock↗

NASA NTRS2011

Assessment of Nutritional Intake During Space Flight and Space Flight Analogs

Background: Maintaining adequate nutrient intake in microgravity is important not only to meet health maintenance needs of astronauts but also to help counteract the negative effects of space flight. Beyond this, food provides psychosocial benefits throughout a mission. Objective: The purpose of this presentation is to discuss dietary intake data from multiple space programs, including Space Shuttle and the International Space Station. Description: These data arise from medical monitoring of both dietary intake and crew health, as well as research protocols designed to assess the role of diet in counteracting bone loss and other health concerns. Ground-based studies are conducted to better understand some of the negative issues related to space flight. Examples of these analog studies are extended bed rest studies, vitamin D supplementation studies in Antarctica, and saturation diving missions on the floor of the ocean. Methods and findings will be presented describing the use of weighed records, diet diaries, and food frequency questionnaires in these various environments. Provision of food and nutrients in spaceflight is important for many body systems including cardiovascular, musculoskeletal, endocrine, immune, and others. Some key areas of concern are loss of body mass, bone and muscle loss, radiation exposure, nutrient intakes during spacewalks, depletion of nutrient stores, and inadequate dietary intake. Initial experimental research studies using food and nutrition as a countermeasure to aid in mitigating these concerns are underway. Conclusion: Beyond their importance for the few individuals leaving the planet, these studies have significant implications for those remaining on Earth.

Rice, Barbara L.↗

NASA NTRS2007

Bisphosphonate Treatment: Risk Management in Long Duration Spaceflight

Bisphosphonates are a class of pharmaceuticals used to treat diverse bone disorders such as osteoporosis, Paget's disease, and multiple myeloma. They constitute a class of drugs which adhere to bony surfaces and interfere with the resorptive activity of osteoclasts. They also represent a potential countermeasure towards the loss of bone mass experienced by astronauts during spaceflight. Recently, the medical literature has revealed cases of osteonecrosis of the jaw in individuals receiving intravenous bisphosphonate therapy with a smaller number of cases occurring in individuals receiving the oral form of the medication. Risk management for long duration missions requires consideration of mission success and lifetime health care of astronauts. We performed MEDLINE and PubMed searches (1966 December 2006) using the following keywords: osteonecrosis, jaw, bisphosphonates. Additional references were obtained from the citations of the retrieved articles. Injectable bisphosphonates such as pamidronate and zoledronic acid have been highlighted recently in the literature due to a possible link with osteonecrosis of the jaw. The mechanism of action remains unclear but may be linked to physiologic microdamage in the jawbones resulting from suppression of bone metabolism. The most predisposing factors appear to be the type and dose of bisphosphonate used, a history of dental surgery, trauma, and/or dental infection. In addition, patients diagnosed with a malignancy such as breast cancer or multiple myeloma, who have been on intravenous bisphosphonate therapy for several months seem to be at increased risk. The use of oral bisphosphonates appears to place patients more at risk from acute events such as gastrointestinal tract injury or perforation. Although some studies report little to no increase in GI events compared to placebo, we must remember that in microgravity, astronauts may be unable to comply with medication instructions. They may have difficulty remaining upright for the required 30-45 minutes post-ingestion. We are currently unaware if this inability to comply with instructions on the package insert may lead to an increased risk for GI events. There is a potential long-term complication that resides with both forms of bisphosphonate therapy. In order to repair normally occurring physiologic microdamage to bone, both osteoclastic resorption and osteoblastic bone deposition must be functional. Controversy exists in the literature regarding whether prolonged use of bisphosphonates may lead to the suppression of bone turnover and accumulation of microdamage. Bisphosphonates are a powerful class of drugs that suppress bone turnover, but may cause serious adverse clinical events such as gastrointestinal tract injury or osteonecrosis of the jaw. Unfortunately, little to no data exists currently which may help us provide answers regarding the risks of their use in a healthy astronaut cohort. While controversy exists in the literature regarding their mechanism and long-term consequences, the potential mission impact or lifetime health care impact of an adverse clinical event resulting from bisphosphonate therapy must be considered.

Fogarty, Jennifer A.↗

NASA NTRS1998

Comparison of Upright Gait with Supine Bungee-Cord Gait

Running on a treadmill with bungee-cord resistance is currently used on the Russian space station MIR as a countermeasure for the loss of bone and muscular strength which occurs during spaceflight. However, it is unknown whether ground reaction force (GRF) at the feet using bungee-cord resistance is similar to that which occurs during upright walking and running on Earth. We hypothesized-that the DRAMs generated during upright walking and running are greater than the DRAMs generated during supine bungee-cord gait. Eleven healthy subjects walked (4.8 +/- 0.13 km/h, mean +/- SE) and ran (9.1 +/- 0.51 km/h) during upright and supine bungee-cord exercise on an active treadmill. Subjects exercised for 3 min in each condition using a resistance of 1 body weight calibrated during an initial, stationary standing position. Data were sampled at a frequency of 500Hz and the mean of 3 trials was analyzed for each condition. A repeated measures analysis of variance tested significance between the conditions. Peak DRAMs during upright walking were significantly greater (1084.9 +/- 111.4 N) than during supine bungee-cord walking (770.3 +/- 59.8 N; p less than 0.05). Peak GRFs were also significantly greater for upright running (1548.3 +/- 135.4 N) than for supine bungee-cord running (1099.5 +/- 158.46 N). Analysis of GRF curves indicated that forces decreased throughout the stance phase for bungee-cord gait but not during upright gait. These results indicate that bungee-cord exercise may not create sufficient loads at the feet to counteract the loss of bone and muscular strength that occurs during long-duration exposure to microgravity.

Boda, Wanda L.↗

NASA NTRS2007

Simulated Microgravity Regulates Gene Transcript Profiles of 2T3 Preosteoblasts: Comparison of the Random Positioning Machine and the Rotating Wall Vessel Bioreactor

Microgravity of spaceflight induces bone loss due in part to decreased bone formation by osteoblasts. We have previously examined the microgravity-induced changes in gene expression profiles in 2T3 preosteoblasts using the Random Positioning Machine (RPM) to simulate microgravity conditions. Here, we hypothesized that exposure of preosteoblasts to an independent microgravity simulator, the Rotating Wall Vessel (RWV), induces similar changes in differentiation and gene transcript profiles, resulting in a more confined list of gravi-sensitive genes that may play a role in bone formation. In comparison to static 1g controls, exposure of 2T3 cells to RWV for 3 days inhibited alkaline phosphatase activity, a marker of differentiation, and downregulated 61 genes and upregulated 45 genes by more than two-fold as shown by microarray analysis. The microarray results were confirmed with real time PCR for downregulated genes osteomodulin, bone morphogenic protein 4 (BMP4), runx2, and parathyroid hormone receptor 1. Western blot analysis validated the expression of three downregulated genes, BMP4, peroxiredoxin IV, and osteoglycin, and one upregulated gene peroxiredoxin I. Comparison of the microarrays from the RPM and the RWV studies identified 14 gravi-sensitive genes that changed in the same direction in both systems. Further comparison of our results to a published database showing gene transcript profiles of mechanically loaded mouse tibiae revealed 16 genes upregulated by the loading that were shown to be downregulated by RWV and RPM. These mechanosensitive genes identified by the comparative studies may provide novel insights into understanding the mechanisms regulating bone formation and potential targets of countermeasure against decreased bone formation both in astronauts and in general patients with musculoskeletal disorders.

Patel, Mamta J.↗

NASA NTRS2014

Role of Oxidative Damage in Radiation-Induced Bone Loss

During prolonged spaceflight, astronauts are exposed to both microgravity and space radiation, and are at risk for increased skeletal fragility due to bone loss. Evidence from rodent experiments demonstrates that both microgravity and ionizing radiation can cause bone loss due to increased bone-resorbing osteoclasts and decreased bone-forming osteoblasts, although the underlying molecular mechanisms for these changes are not fully understood. We hypothesized that excess reactive oxidative species (ROS), produced by conditions that simulate spaceflight, alter the tight balance between osteoclast and osteoblast activities, leading to accelerated skeletal remodeling and culminating in bone loss. To test this, we used the MCAT mouse model; these transgenic mice over-express the human catalase gene targeted to mitochondria, the major organelle contributing free radicals. Catalase is an anti-oxidant that converts reactive species, hydrogen peroxide into water and oxygen. This animal model was selected as it displays extended lifespan, reduced cardiovascular disease and reduced central nervous system radio-sensitivity, consistent with elevated anti-oxidant activity conferred by the transgene. We reasoned that mice overexpressing catalase in mitochondria of osteoblast and osteoclast lineage cells would be protected from the bone loss caused by simulated spaceflight. Over-expression of human catalase localized to mitochondria caused various skeletal phenotypic changes compared to WT mice; this includes greater bone length, decreased cortical bone area and moment of inertia, and indications of altered microarchitecture. These findings indicate mitochondrial ROS are important for normal bone-remodeling and skeletal integrity. Catalase over-expression did not fully protect skeletal tissue from structural decrements caused by simulated spaceflight; however there was significant protection in terms of cellular oxidative damage (MDA levels) to the skeletal tissue. Furthermore, we used an array of countermeasures (Antioxidant diets and injections) to prevent the radiation-induced bone loss, although these did not prevent bone loss, analysis is ongoing to determine if these countermeasure protected radiation-induced damage to other tissues.

oxidative damage↗

NASA NTRS2003

Excercise Within LBNP as an Artificial Gravity Countermeasure

Previous exercise in space has lacked sufficient loads to maintain preflight cardiovascular and musculoskeletal mass and function. Lower body negative pressure (LBNP) produces a static force equivalent to one Earth body weight by each 52 mm Hg of LBNP during supine posture. LBNP also provides transmural blood pressures simulating upright exercise. Thus, this artificial-gravity concept may help maintain cardiovascular and musculoskeletal systems of crewmembers during prolonged exposure to microgravity. Currently available, bungee cord assisted, treadmill exercise is limited by harness discomfort, lower than normal loads, abnormal post-flight gait, and the absence of gravitational blood pressures within the vascular system. PURPOSE: This project evaluates a method to create artificial gravity using supine LBNP treadmill exercise to prevent loss of physiologic function in microgravity simulated by 30 days of bed rest. Identical twins were used as volunteers so that statistical power could be maximized. This countermeasure is being transitioned to space flight. CURRENT STATUS OF RESEARCH Methods: Six sets of identical twins (6 females and 14 males, 21-36 years) remained in 6 head-down tilt (HDT) bed rest for 30 days to simulate prolonged microgravity. Six subjects were randomly selected to exercise supine in an LBNP chamber for 40 minutes six days per week (EX group), while their twin brothers served as non-exercise controls (CON). Pressure within the exercise LBNP chamber was adjusted to increase load, hence increasing exercise intensity. During supine treadmill exercise, LBNP (52-63 mmHg) was applied to produce foot ward forces equivalent to those for upright running on Earth at 1.0-1.2 times body weight (BW) and subjects performed an interval exercise protocol (40-80% peak exercise capacity [VO2pk]). Five minutes of resting LBNP immediately followed each exercise session. Results: Orthostatic tolerance time decreased significantly after 30 days bed rest in the CON group, but was relatively maintained in the EX group. VO2pk was maintained in EX males, but not in CON males. Isokinetic knee strength (extension, peak torque) decreased significantly in CON males, but was preserved in EX males. The EX group had significantly higher spine muscle strength after bed rest than the CON group. The cross-sectional area of spinal muscle at L4/5 level decreased significantly in the CON group but not in the EX group. Urinary n-telopeptide excretion, an index of bone resorption, was increased during bed rest in CON, but not in EX subjects. This suggests protection by LBNP exercise against the increase in bone resorption typically seen in simulated and actual microgravity. Significant changes in bone mineral density (BMD) in the spine and ribs were observed in CON subjects, but not in EX subjects. Conclusions: Our treadmill exercise protocol within LBNP plus a short period of post-exercise LBNP maintains orthostatic responses, upright exercise capacity and other important physiologic parameters during bed rest. These results document the efficacy of our apparatus and exercise protocol for maintaining physiologic structure and function during long-duration microgravity as simulated by 30 days of HDT bed rest. FUTURE PLANS: More sets of female identical twins are needed to reach significance. The LBNP exercise chamber will be redesigned for flight.

Hargens, A. R.↗

NASA NTRS2002

Nutrition and renal stone disease in space

There is a growing body of evidence from the National Aeronautics and Space Administration and the Russian space program showing that humans exposed to the microgravity environment of space have a greater risk for developing renal stones. Increased bone resorption and the attendant hypercalciuria and hyperphosphaturia contribute significantly to raising the urinary state of saturation with respect to the calcium salts, namely calcium oxalate and calcium phosphate. In addition, other environmental and dietary factors may adversely affect urine composition and increase stone formation risk during space flight. For example, reductions in urinary volume, pH, and citrate contribute to raising stone formation risk. In addition to raising the risk for calcium stone formation, this metabolic profile is conducive to the formation of uric acid stones. Although observations to date have suggested that there may actually be a reduced food intake during the early phase of flight, crew members on longer-duration flights may increase food intake and be at increased risk for stone formation. Taken together, these findings support the use of nutritional recommendations for crew members that would serve to reduce the stone-forming propensity of the urinary environment. Pharmacologic intervention should be directed at raising urinary volumes, diminishing bone losses, and preventing reductions in urinary pH and citrate. Success in reducing the risk for stone formation in astronauts would also be of potential major benefit to the estimated 20 million Americans with nephrolithiasis.

Review↗

NASA NTRS1999

Bone Blood Flow During Simulated Microgravity: Physiological and Molecular Mechanisms

Blood flow to bone has been shown to affect bone mass and presumably bone strength. Preliminary data indicate that blood flow to the rat femur decreases after 14 days of simulated microgravity, using hindlimb suspension (HLS). If adult rats subjected to HLS are given dobutamine, a synthetic catecholamine which can cause peripheral vasodilation and increased blood flow, the loss of cortical bone area usually observed is prevented. Further, mechanisms exist at the molecular level to link changes in bone blood flow to changes in bone cell activity, particularly for vasoactive agents like nitric oxide (NO). The decreases in fluid shear stress created by fluid flow associated with the shifts of plasma volume during microgravity may result in alterations in expression of vasoactive agents such as NO, producing important functional effects on bone cells. The primary aim of this project is to characterize changes in 1) bone blood flow, 2) indices of bone mass, geometry, and strength, and 3) changes in gene expression for modulators of nitric oxide activity (e.g., nitric oxide synthase) and other candidate genes involved in signal transduction of mechanical loading after 3, 7, 14, 21, and 28 days of HLS in the adult rat. Using a rat of at least 5 months of age avoids inadvertently studying effects of simulated microgravity on growing, rather than adult, bone. Utilizing the results of these studies, we will then define how altered blood flow contributes to changes in bone with simulated microgravity by administering a vasodilatory agent (which increases blood flow to tissues) during hindlimb suspension. In all studies, responses in the unloaded hindlimb bones (tibial shaft, femoral neck) will be compared with those in the weightbearing humeral shaft and the non-weightbearing calvarium (skull) from the same animal. Bone volumetric mineral density and geometry will be quantified by peripheral quantitative CT; structural and material properties of the long bones will be determined by 3-point bending (tibia, humerus) or compression (femoral neck) testing to failure. A unique aspect of these studies will be defining the time course of changes in gene expression in bone cell populations with unloading, accomplished with Northern blots, in situ hybridization, and immunohistochemistry. These studies have high relevance for concurrent protocols being proposed by investigators on NSBRI Cardiovascular and Muscle teams, with blood flow data available on a number of tissues other than bone. Further, dobutamine and other Beta-agonists have been tested as countermeasures for altered muscle and cardiovascular function. Results of the intervention tested in our studies have potential relevance for a number of systemic changes seen with prolonged spaceflight.

Bloomfield, Susan A.↗

NASA NTRS1997

The Kinematics of Treadmill Locomotion in Space

Locomotion on a treadmill in 0 G will probably remain a centerpiece of NASA's exercise countermeasures programme. This form of physical activity has the potential to cause large bone and muscle forces as well as loading during a period of continuous treadmill exercise. A critical concern is the provision of a treadmill which can approximate 1 G performance in space. At this point, no adequate objective measurements of in-flight treadmill kinetics or of the human response to this activity have been made. Interpretation of the results obtained in the present study is limited by the following: (1) bungee tensions were not measured; (2) ground reaction forces were not measured in parallel with the kinematic measurements; and (3) the instrumentation used to film the astronauts could itself have been affected by microgravity. Despite these shortcomings, what is apparent is that exercise during NASA missions STS 7 and STS 8 resulted in leg motions that were similar to those found during 1 G locomotion on an inclined passive treadmill and on an active treadmill at an even steeper grade. In addition, it was apparent that the majority of the loads were transmitted through the forefoot, and one can surmise that this style of running would result in physiologically significant tensions in the calf musculature and resultant ankle compressive loading. Further speculation regarding limb loading is complicated by the fact that varying amounts of force are transmitted through (1) the treadmill handle and (2) bungee cords that act as a tether. New generations of treadmills are being manufactured that could provide I important information for planners of long-duration space missions. If these types of treadmill are flown on future missions, it will be possible to control bungee tensions more precisely, control for grade and speed, and, most importantly, provide data on the rates and magnitudes of limb loading. These data could then be incorporated into biomechanical models of the lower limb to more fully understand mechanisms of load transmission from distal to proximal structures and to optimize in-flight exercise protocols in such a way that muscle and bone loss could be reduced.

Thornton, W. E.↗